so are they…

Posted on Friday 25 July 2014

By Thomas Insel
July 22, 2014

It’s difficult to overstate the impact that genomic medicine is having on biomedical research and practice. For cancer diagnostics, rare disease therapeutics, and fields like microbiomics and infectious diseases, the advent of cheap, fast, precise genomic sequencing has been a game changer. What about mental disorders? There has been a lot of hype about genomics revolutionizing diagnosis or treatment of mental disorders, but is there any real hope that the kind of advances that have helped patients in the rest of medicine will help people with autism or schizophrenia or mood disorders?

The history of psychiatric genomics has been, until recently, disappointing. The search for candidate genes—such as those, like the serotonin transporter gene, suspected to be contributors to risk because of their role in medication response—led to many papers but few replications and no actionable findings. Unbiased scans of the whole genome were challenging because there is so much variation in the genome, most of which is unrelated to risk or resilience. To detect a signal from all of this background noise, one would need many thousands of samples. Over the past five years, as the field realized the need for larger numbers of samples, investigators from around the world have worked together to share results in the hope of attaining the statistical power needed to find variants associated with schizophrenia or autism. New findings demonstrate that sharing data does indeed lead to exciting results.

A report in Nature this week from the Psychiatric Genomics Consortium, a team of investigators in more than 80 institutions across 25 countries, looks at common variation (variation present in 10 percent of the general population) in nearly 37,000 cases of schizophrenia and over 113,000 controls. This genome wide association study revealed 108 different loci where variations were associated with schizophrenia; 83 of these had not been reported previously. Note, these are not “108 genes for schizophrenia.” These are areas of the genome where variations in sequence are associated with schizophrenia. Most of these are not in or even near genes. And any one of these 108 regions contributes only a tiny fraction of risk in the population. Nevertheless, this is a major step forward in describing the genetic risk for schizophrenia…
I would join Dr. Insel in acknowledging that whatever the Psychiatric Genomics Consortium is reporting in this recent Nature article is likely a step forward in genetic research, something important. I’ll probably even look into what that article actually reports. Maybe it will someday help us predict coming psychosis, and in some even more distant iteration become a part of doing something about it. But whatever its importance, there’s plenty of schizophrenia around that we don’t need any fancy new genetic tests to locate. It’s right there on the streets of just about any city in America. And some of the people we used to call patients are now occupying a growing space in our correctional facilities – labeled inmates. Neuroscience and genomics are important, but so are they.

It would be unfair to blame Dr. Insel’s NIMH for the deplorable state of the our care of the severely mentally ill in this country. But it’s not at all off base to expect him to mention their presence, to focus the NIMH on studying solutions, to lobby for them with the same energy and enthusiasm he puts into the B.R.A.I.N. initiative, or his Translational whatevers, or the unborn psychotic people. For the moment, his Clinical Neuroscience is more or less a hypothetical discipline except for a group of medications that have been around for six decades. And as Dr. Frances said in his blog mentioned in my last post [join the cry…]:
While we chase the receding holy grail of future basic science breakthrough, we are shamefully neglecting the needs of patients who are suffering right now. It is probably on average worse being a patient with severe mental illness in the US now than it was 150 years ago. It is certainly much worse being a patient with severe mental illness in the US as compared to most European countries. Access to community care and decent housing is deteriorating; hundreds of thousands of psychiatric patients are homeless or in prison…
I’ll have to admit that I lost all hope for Dr. Insel several years ago when I read this particular Director’s Blog post:

By Thomas Insel

NIMH, like all Institutes at NIH, has an advisory council that meets three times each year. The National Advisory Mental Health Council (NAMHC) is a distinguished group of scientists, advocates, clinicians, and policy experts. Each of our meetings includes a closed session to review individual grants considered for funding and a session open to the public that engages this diverse group in discussions about the larger issues that guide NIMH funding. At last week’s session, we heard a recurrent tension around one such larger issue. Some members of Council bear witness to the poor quality of care, the unmet medical need, and the diminishing investments by states on behalf of people with mental disorders. They reasonably ask, “How are we ensuring that the science that NIMH has produced is implemented where the need is greatest?”…
His conclusion was clear:
Let us hope we don’t short-change our grandchildren, sixty years from today, by failing to invest in the long-term promise of more effective diagnostics and therapeutics for mental disorders.
I’m not going to bother to summarize what he said in that post. I’ve already done that [the first Lemming…], but the point is that he blew them off. That’s what he always does. He presents both sides in such a way to give the impression that he’s being like Solomon, but he doesn’t cut the baby in half. He keeps it all for himself and his dreams and doesn’t change gears [the most recent example of that technique was in his Are Children Overmedicated?]. So long as Dr. Insel remains in his position, the NIMH will continue with its monocular focus on the narrow window of his neuroscience interests and many of our severely ill mental patients will continue to live in whatever dark spaces they can find…
    July 25, 2014 | 9:11 PM

    Genomics is the new astrology. Find correlations and assume they are causal. Then “discover” the causality by proving what has already been assumed.

    Astrology: Find correlations with the sun sign. Those that don’t hold up, add in the moon sign. Still not enough of a p value what’s in retrograde? Eventually end up circling UrAnus.

    Events generated by a stochastic process cluster. To experience this roll a die 200 times and record the results of each roll. Then look at the occurrence pattern of any outcome, say 6. The pattern will not appear random. But the process that spawned the “non-random” pattern was random.

    Its the same way with genomics and all the “big-data” searches for correlations. The underlying processes are stochastic and the correlations are simply accidents. Adding more data, using more precise measurements are all just generating astrological nonsense.

    July 25, 2014 | 10:43 PM

    Lately, I’ve been thinking about a “talk” I had with a “mentally ill’ man when I was 12. My family was visiting an uncle in the V.A. hospital in Waco, Texas. I went out to get some air and take a break from my uncle, then met a man who told me all about a pink suit he had at home. “I have a pink hat. I have a pink shirt. I have a pink tie…”, and so on, including jacket, pants, socks, belt, shoes.

    We were standing on big porch at the top of some stairs on a crisp, cool, sunny day. And that’s what the “talk” felt like. It was amazing, and it never occurred to me to be afraid of him— I just looked him in the eye and gave him my full attention. The suit he described appeared to be what he was wearing at the time, but it was all lime green— all the same lime green, in fact. After he finished describing his suit, I smiled and made a silent gesture to let him know I had to leave. He tipped his hat. I smiled ‘goodbye’ and I’ve relished the memory since.

    The older I got and the more I learned about fabrics and dies, the more amazing that man’s suit got. Making all those completely different materials in his ensemble the same green and/or pink was the work of a true master.

    I always wondered if he had made it, or if someone else did it for him. My uncle had an amazing Court Jester’s outfit— it was red and white satin with the heart reversed on the chest. It was worthy of a Broadway show— it was very well done. There is often a certain kind of creative competence in those who have to navigate the world as “mentally ill” in the eyes of others.

    Maybe people in mental crises and/or people who are too alienated and hurt to function “normally” would benefit from more people just relaxing and going with the flow when dealing with someone who is clearly not “normal”, but not visibly threatening. Pretending like they don’t exist or calling them “diseased” while insisting that that removes stigma, does nothing to let the dispossessed know that they have a place in this world and are ‘one of us’ and even worthy of a little pleasant conversation now and then.

    berit bryn jensen
    July 26, 2014 | 6:35 AM

    Good article. Good comments. Thanks to Joseph Arpaia, Wiley and the always relevant boringoldman.
    Looking at the pictures on top I am struck by how they could have illustrated this saturday morning’s news from Gaza, pictures of bottomless grief, despair, shock.
    Looking for answers in the genomics of the politicians responsible for massacres then and now can hardly enlighten us to the whys of their evil. But their histories and increasing callousness to the suffering of others can, I think. Insel is a basket case for the danger of living safely within one’s chosen abstractions.

    James O'Brien, M.D.
    July 26, 2014 | 4:34 PM

    Let’s be fair. Genomics is sometimes pathognomonic sometimes actuarial. It varies disease by disease or disorder. When it comes to Huntingdon’s or Rett’s (which DSM-5 omitted, because after all, we can’t have a mental disorder with a rock solid cause), genetics is everything. When it comes to most mental disorders, it’s actuarial. Increased or decreased odds, but nothing definitive.

    James O'Brien, M.D.
    July 26, 2014 | 9:36 PM

    Nonetheless, a country with a shoddy mental health system for the severely ill taking on a grandiose high tech project like this makes no sense when ignoring the basics. Especially when genetic studies are going to be funded anyway through different sources.

    This is pretty much like North Korea announcing plans to put a man on Mars.

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